Abstract: Diabetic retinopathy is a common complication of diabetes characterized by progressive neurovascular injury and the consequent retinal function deterioration. Currently there are no therapies that can effectively protect retinal neurons, and thereby mitigate, or reverse, the visual dysfunction in diabetic patients. Developing such therapies is an urgent and unmet need for the field. In the previous funding period, we identified that X-box binding protein 1 (XBP1), a stress-inducible transcription factor, plays a central role in retinal cell adaptation to chronic stressors in aging and diabetes. Conditional knockout (cKO) of XBP1 in the retina results in accelerated retinal function decline, loss of retinal neurons, disruption of synapses, and aberrant microglia activation in the retina with aging. Importantly, we found that XBP1 expression in the aging retina is gradually decreased and activation of XBP1 in response to endoplasmic reticulum (ER) stress is reduced. We reasoned that the loss of XBP1 impairs the ability of retinal cells to adapt to chronic stresses in aging, ultimately leading to neuronal damage. We tested whether XBP1 is involved in neuronal adaptation to chronic stresses in diabetes. We found that loss of XBP1 leads to early onset retinal function decline, neuronal loss, and enhanced Mller glia activation in diabetic mice. Based on these findings, we hypothesize that XBP1-mediated stress response signaling is crucial to maintaining functional and structural integrity of retinal neurons under naturally occurring or pathogenic chronic stress conditions, thus, protecting against neurodegeneration in diabetes and aging. In current application, we will delineate how XBP1 regulates retinal neuronal adaptation to metabolic stress in diabetes. In particular, we will explore the mechanisms by which XBP1 protects retinal neurons through regulation of aerobic glycolysis in photoreceptor cells. Taking advantage of the innovative technology of vis-OCT for retinal imaging, we will identify the earliest change in retinal nerve fiber layer (RNFL) before any detectable retinal ganglion cell loss in diabetic retinas. We will also measure the precise change of retinal metabolic rate of oxygen for a comprehensive characterization of metabolic profiling of retinal neurons in diabetes. The in-depth information generated from the proposed studies will fill the knowledge gap in understanding the role of aerobic glycolysis and its regulation by XBP1 in retinal neuropathy in diabetes. In addition, our study to identify novel molecules that regulate retinal neuronal metabolism will pave the way for new treatment to protect retinal neurons in diabetic retinopathy.